How native metal-binding sites accommodate uranyl: a comparative study of human serum transferrin, human serum...

Understanding how the uranyl ion (UO₂²⁺) exploits native metal-binding sites in human proteins is essential for elucidating uranium transport, accumulation, and toxicity. In this computational study, we investigated how uranyl is accommodated within the protein pockets of human serum transferrin and human serum albumin, and compared these interactions with those in an engineered super uranyl-binding protein (SUP). QM/MM geometry optimizations and harmonic vibrational frequency calculations were performed starting from available X-ray crystal structures. The intrinsic strengths of individual uranyl-protein interactions were quantified using Local Vibrational Mode Analysis (LMA), complementary with Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbital (NBO) analyses. Histidine residues form the strongest individual U-N interactions, whereas aspartate and glutamate provided equally strong or stronger capture through bidentate U-O coordination. In human serum transferrin, the native carbonate cofactor forms an important component of the uranyl coordination sphere, whereas hydrogen bonds involving the uranyl oxo atoms contributed only weakly to binding. Comparison with the high-affinity SUP revealed that human serum proteins bind uranyl nearly as strongly as the engineered protein, highlighting their potential role in uranium transport and fate following human exposure.